Specific bone region localization of osteolytic versus osteoblastic lesions in a patient-derived xenograft model of bone metastatic prostate cancer

Objective:Bone metastasis occurs in up to 90%of men with advanced prostate cancer and leads to fractures,severe pain and therapy-resistance.Bone metastases induce a spectrum of types of bone lesions which can respond differently to therapy even within individual prostate cancer patients.Thus,the special environment of the bone makes the disease more complicated and incurable.A model in which bone lesions are reproducibly induced that mirrors the complexity seen in patients would be invaluable for pre-clinical testing of novel treatments.The microstructural changes in the femurs of mice implanted with PCSD1,a new patient-derived xenograft from a surgical prostate cancer bone metastasis specimen,were determined.Methods:Quantitative micro-computed tomography(micro-CT)and histological analyses were performed to evaluate the effects of direct injection of PCSD1 cells or media alone(Control)into the right femurs of Rag2
/
gc
/
male mice.Results:Bone lesions formed only in femurs of mice injected with PCSD1 cells.Bone volume(BV)was significantly decreased at the proximal and distal ends of the femurs(p<0.01)whereas BV(p<0.05)and bone shaft diameter(p<0.01)were significantly increased along the femur shaft.Conclusion:PCSD1 cells reproducibly induced bone loss leading to osteolytic lesions at the ends of the femur,and,in contrast,induced aberrant bone formation leading to osteoblastic lesions along the femur shaft.Therefore,the interaction of PCSD1 cells with different bone region-specific microenvironments specified the type of bone lesion.Our approach can be used to determine if different bone regions support more therapy resistant tumor growth,thus,requiring novel treatments.

Study on the mechanism of"Sangu Decoction"in the treatment of bone metastatic carcinoma

Objective:To study the mechanism of"Sangu Decoction"in the treatment of bone metastatic carcinoma by network pharmacology.Methods:TCMSP,TCMID and TCM Database@Taiwan databases and literature search were used to screen the main effective components of drugs.Swiss Target and TCMSP databases were used to search the potential therapeutic targets of"Sangu Decoction".DisGeNet and Drugbank databases were used to search the genes of bone metastatic carcinoma.Drug action targets and disease genes were mapped.Cytoscape 3.8.1 software was used to visualize and screen out the core genes.GO and KEGG pathway analysis was performed on potential therapeutic targets.Results:There were 29 main active ingredients in"Sangu Decoction",which contained 413 target proteins.There are 773 disease targets of bone metastatic carcinoma,of which 112 are potential targets of"Sangu Decoction"for the treatment of bone metastatic carcinoma.Through GO and KEGG pathway analysis,it was found that"Sangu Decoction"exerted anti-cancer,inhibiting bone metastasis and immune regulation mechanism through TNF,ErbB,FoxO,PI3K-Akt,Toll-like Receptor,NOD-like Receptor,Rap1 and other signaling pathways in the treatment of bone metastatic carcinoma.The key genes of"Sangu Decoction"in treating bone metastatic carcinoma are VEGFA,AKT1,IL6,TP53,MAPK3,SRC,EGFR and CASP3 and so on.Conclusion:In this study,we constructed a a multi-level interaction"traditional Chinese medicine-compound-target-pathway"network through network pharmacology,and found that the mechanism of"Sangu Decoction"in the treatment of bone metastasis cancer involves multiple targets and pathways,which may be related to anti-cancer,inhibition of bone metastasis,regulation of immunity and so on.

Effects of Curcumin on Biological Behavior and NF-κB/TNF-α Pathway in Mice with Metastatic Bone Pain of Breast Cancer Induced by Walker 256 Cells

Background. The active ingredient curcumin of traditional Chinese medicine was selected as the research object to investigate the possible mechanism of breast cancer metastatic bone pain in mouse walker 256 cells and the effect of curcumin on the NF-κB/TNF-α pathway in order to provide a new idea for clinical treatment of breast cancer metastatic bone pain. Methods. By establishing an animal model of breast cancer bone metastasis in walker 256 cells, the biological behavior of nude mice was observed on the 8th day after successful modeling. Meanwhile, the low dose group, middle dose group and high dose group of mice were given 15 mg/kg, 25 mg/kg, 50 mg/kg of curcumin solution intraperitoneally in 21 days, and the right cavity bone and spinal cord distended in mice (L4-L6) tissues were used to detect related factors, Immunohistochemical method was used to detect c-fos in spinal cord. Expression levels of RANK, NF-κB and TNF-α were detected by RT-PCR and Western blot. Meanwhile, serum levels of Cox2, il-6, leukotriene and PGE2 were detected. Results. Observing the biological behavior index of nude mice, we found that the mechanical pain and thermal pain threshold decreased (p < 0.05), and the cold pain and spontaneous pain scores increased significantly (p < 0.05). After group study, the expression of c-fos in the cancer pain model group was significantly higher than that in the normal control group (p < 0.05), and with the increase of curcumin dose, the expression of c-fos in the high dose group was significantly lower than that in the solvent model group (p < 0.05). The expression of RANK, NF-κB, TNF-α was higher than that of the normal control group and decreased gradually with the increase of curcumin dose, among which the expression of high dose group was significantly lower than that of solvent group (p < 0.05). RANK, NF-κB, TNF-α protein expression was higher than that of normal control group and gradually decreased with the increase of curcumin dose. The levels of Cox2, IL-6, leukotriene and PGE2 in serum decreased with the increase of curcumin dose, and the high dose group decreased significantly (p < 0.05). Conclusions. On the 8th day after the success of the animal model of breast cancer bone metastasis in Walker 256 cells, abnormal biological behaviors such as heat pain, cold pain sensation and spontaneous hyperalgesia were observed. Further studies have found that the increased expression of rank on osteoclasts induced up-regulated expression of NF-κB and c-fos, induced expression of TNF-α gene, and could induce synthesis and release of leukotriene, PGE2 through direct activation of cyclooxygenase, inflammatory media IL-6 cascade reaction, resulting in pathological pain and hypersensitivity. Traditional Chinese medicine active ingredient curcumin could reduce RANK expression of osteoclast, inhibit cell NF-κB and spinal cord c-fos activity, reduce TNF-α expression, inhibit Cox2 activity, and reduce the synthesis and release of inflammatory factors leukotriene and PGE2, thus exerting its analgesic effect, which provides new ideas and methods for clinical treatment of metastatic bone pain in breast cancer.

Surgical treatment of metastatic bone disease of the distal extremities

Metastatic bone disease of the distal extremities,also known as acrometastasis,is very rare.Thus,there is very limited information regarding the clinical manifestations and methods of surgical treatment.The current available literature shows that acrometastases are often encountered in the context of advanced disease and are thus associated with poor patient survival.As metastatic bone disease is generally uncurable,the goal of surgical treatment is to provide the patient with good function with as few complications as possible.In this article,we discuss the clinical manifestation of acrometastases,the methods of surgical intervention,and the expected clinical outcome.Non-surgically managed pathological fractures generally remain ununited;therefore,conservative treatment is reserved for patients with poor general condition or dismal prognosis.The current evidence suggests that in lesions of the lower arm and leg,osteosynthesis(plate and screw fixation or intramedullary nail)is the most common method of reconstruction,whereas local excision or amputation are more commonly used in cases of more distal lesions(such as ankle,foot and hand).Following surgery most patients receive adjuvant radiotherapy,even though its role is poorly documented.Close collaboration between orthopedic surgeons and medical oncologists is necessary to improve patient care and treatment outcome.Further studies are needed in order to provide stronger clinical evidence and improve decision-making,in an effort to optimize the patients’quality of life and avoid the need for revision surgery.

Analysis of therapeutic efficacy of Aredia in treating pain caused by advanced malignant metastatic bone tumors

Objective To study therapeutic efficacy of Aredia in treating malignant metastatic bone tumors. Method 60～90 mg Aredia was administrated iv in 31 cases with malignant metastatic tumors,once each week. Results Pain in 12 cases was significantly relieved.14 cases acquired relif.Total effective rate was 83.9%.Activity ability was improved by 80.6%.No apparent toxicological and adverse effects as well as fever and cold symptoms were observed.Conclusion Aredia is a kind of ideal drugs for treatment of pain caused by malignant metastatic bone tumors.It is convenient in use and could be endured by patients.

Surgical management of metastatic disease of long bone

Objective To improve the life quality of cancer patients with metastasis to long bone and to long bone and to select suitable surgical treatment. Methods Fifty-two patients with metastasis 27 men and 25 women, were June 2003 Vol12 No2 treated from 1990 to 1999. Their average age was 56. 8 years (33 - 74). In 16 patients with multiple lesions, underwent surgery at bone shaft (29 patients) and bone epiphysis (26). Thirty patients were treated for pathologic fracture and the rest for impending fracture. Operations included limb-salvage (51 patients) and amputation (4) Limb salvage consisted of intralesional curettage (3 patients ), intramedullary nailing reconstruction (29 ), endoprosthesis ( 18 ), and temporary spacer ( 1 ). 21 patients accepted postoperative chemotherapy or radiotherapy. Results Follow-up of 52 patients for a mean of 28. 2 months (2 - 122 months) showed pain relief (41 patients), (75%) and full or part weight-bearing stability ( 36 ) 69 % . Local tumor recurrence occurred in 11 patients.

Non-secretory multiple myeloma expressed as multiple extramedullary plasmacytoma with an endobronchial lesion mimicking metastatic cancer:A case report

BACKGROUND Non-secretory multiple myeloma(MM)is a rare condition that accounts for only 3%of MM cases and is defined by normal serum and urine immunofixation and a normal serum free light chain ratio.Non-secretory MM with multiple extramedullary plasmacytomas derived from endobronchial lesions is extremely rare and can be misdiagnosed as metastasis of solid cancer.CASE SUMMARY A 36-year-old man presented with progressive facial swelling and nasal congestion with cough.Various imaging studies revealed an endobronchial mass in the left bronchus and a large left maxillary mass with multiple destructive bone metastatic lesions.He initially presented with lung cancer and multiple metastases.However,pathologic reports showed multiple extramedullary plasmacytomas in the left maxilla and the left bronchus.There was no change in the serum and urine monoclonal protein levels,and no abnormalities were observed in laboratory examinations,including hemoglobin,calcium,and creatinine levels.The bone marrow was hypercellular,with 13.49%plasma cells.The patient was diagnosed with non-secretory MM expressed as multiple extramedullary plasmacytomas with endobronchial lesions in a rare location.Radiation therapy for symptomatic lesions with high-dose dexamethasone was started,and the size of the left maxillary sinus lesion dramatically decreased.In the future,chemotherapy will be administered to control lesions in other areas.CONCLUSION We present a rare case of non-secretory MM with multiple extramedullary plasmacytoma with an endobronchial lesion.

Clinical research on zoledronic acid in treatment of pain caused by bone metastasis of malignant tumors

Objective:To evaluate the efficacy and safety of zoledronic acid for the pain caused by metastatic tumor of bone.Methods:52 patients with metastatic tumor of bone were randomly divided into two groups.The zoledronic acid group received 4 mg zoledronic acid infusion for 30 minutes and the control group received 90 mg pamidronate infusion for 6 hours. Results:The effective rates in zoledronic acid group and control group were 73.08%and 69.23%respectively.No significant difference was observed between the two groups.The median pain relief onset at days 5 and 7,respectively,and no significant difference was observed.The ECOG scores on the 7th day after medication:the differences in the zoledronic acid group before and after medication and between the two groups were both significant(P<0.001 and P=0.0448).The adverse reac- tion was no significant difference between the two groups.Conclusion:Zoledronic acid is efficient and safe in the treatment of pain caused by metastatic tumor of bone and it has low adverse reaction rate and convenient shorter using time.

Clinical and functional comparison of dynamic hip screws and intramedullary nails for treating proximal femur metastases in older individuals

Objective:To compare the outcomes of dynamic hip screws(DHS)and intramedullary nailing(IMN)in the treatment of extra-capsular metastatic carcinoma of the proximal femur.Methods:A retrospective case analysis method was used to examine data of patients with proximal metastatic cancer of the femur who were treated with internal fixation in Department of Orthopaedics,Beijing Friendship Hospital,from January 2007 to December 2018.Blood loss,postoperative pain,functional score,length of stay,and survival rates were compared,and postoperative complications were assessed.Results:Complete follow-up data were available for 33 patients.The mean follow-up period was 12.2±3.6(range:9-32)months and the average age was 72.3±4.7(range:59-83)years old.There were 20 females and 13 males.Twenty-three patients had undergone IMN and 10 DHS,according to bone defects and the patient’s overall condition.The median survival time was 10 months in the IMN group and 11 months in the DHS group.Duration of surgery(t=-7.366,P<0.001)and length of hospital stay(t=-3.509,P<0.001)differed significantly between the two groups.There was one case of breakage of internal fixation in the IMN group.Conclusions:There was no significant difference between DHS and IMN in terms of surgical efficacy.IMN and DHS were different in terms of surgical time and hospital stay.However,due to the limited number of cases in this study,multi-factor analysis has not been performed and needs to be further verified in future analysis.When developing a surgical plan,it is recommended to consider the patient’s condition and the surgeon’s experience.

PANCYTOPENIA AFTER REPEATED RADIOIODINE TREATMENT ON METASTATIC THYROID CANCER TO BONE

The protocol and evaluation of I therapy have already been established, and it is quite effective in general for patients with metastatic thyroid cancer under 40 years old with fine or occult type of pulmonary metastases (papillary adenocarcinoma). However, the response of bone metastasis to I therapy is limited to only a part of tumors and is temporary in most cases although high I accumulation is visualized on scintigram. We have encountered a 65-year-old man with thyroid cancer. At the age of 61, follicular thyroid cancer with multiple bone metastasis was diagnosed, total thyroidectomy was carried out, and subsequently I therapy was performed. Bone pain diminished